Neuropediatrics 2019; 50(S 02): S1-S55
DOI: 10.1055/s-0039-1698232
Poster Presentations
Poster Area GNP Metabolic/Neurodegenerative Disorders
Georg Thieme Verlag KG Stuttgart · New York

Urea Cycle Disorders in the US and Europe – Evidence-based Clinical Outcomes Derived from Two Decades of Experience with Prospective Registry Studies

Roland Posset
1   Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Heidelberg, Abteilung für Neuropädiatrie und Stoffwechselmedizin, Heidelberg, Germany
,
Andrea L. Gropman
2   Children’s National Health System, The George Washington School of Medicine, Washington, District of Columbia, United States
,
Sandesh C. S. Nagamani
3   Baylor College of Medicine and Texas Children’s Hospital, Department of Molecular and Human Genetics, Houston, Texas, United States
,
Lindsay C. Burrage
4   Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas
,
Jirair K. Bedoyan
5   University Hospitals Cleveland Medical Center and Case Western Reserve University, Center for Human Genetics and Department of Genetics and Genome Sciences, Cleveland, Ohio, United States
,
Derek Wong
6   University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California, United States
,
Gerard T. Berry
7   Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Matthias R. Baumgartner
8   University Children’s Hospital, Children’s Research Center Zurich, Zurich, Switzerland
,
Marc Yudkoff
9   University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
,
Matthias Zielonka
10   University Hospital Heidelberg and Heidelberg Research Center for Molecular Medicine (HRCMM), Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
,
Georg F. Hoffmann
11   University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
,
Peter Burgard
11   University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
,
Magdalena E. Kowoll
11   University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
11 September 2019 (online)

 
 

    Background: Urea cycle disorders (UCDs) are a group of rare inherited neurometabolic diseases with an estimated cumulative prevalence of 1 in 35,000 to 52,000 newborns presenting with life-threatening symptoms within the first 28 days of life or with heterogeneous symptoms (e.g. developmental, neurological and intellectual disabilities) any time after the newborn period. Growing clinical awareness for UCDs, development of diagnostic and therapeutic recommendations, and the implementation of national newborn screening programs hold out the potential for improved clinical outcome.

    Aim: To evaluate the impact of current diagnostic and therapeutic strategies on the neurocognitive outcome of individuals with UCDs.

    Materials and Methods: This prospective, observational, transatlantic, multicentre study includes data from 1,095 individuals from the two largest registries for UCDs, i.e. the North American Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). 503 individuals with a cumulative follow-up of 702 patient-years received comprehensive cognitive testing. z-scores were calculated using the normative data of each psychological test

    Results: Non-interventional variables, such as UCD subtype, early disease onset and height of initial peak plasma ammonium concentration are predictors of intellectual disability (z < -2.0). Protection of cognitive abilities is related to early detection by newborn screening and timely liver transplantation. Importantly, none of the currently used nitrogen scavengers (sodium-/glycerol-phenylbutyrate or sodium benzoate) appeared superior with regard to long-term neurocognitive outcome of specific individuals with UCDs.

    Discussion: Combining data from registry studies (UCDC and E-IMD) is a powerful tool to provide evidence-based information in the field of rare neurometabolic disorders. Moreover, it is a prerequisite to identify important indicators of neuroprotection and thus, to analyze the impact of current treatment principles. Confirmation in a longitudinal manner will provide evidence-based recommendations that can be translated to patient care. Future clinical trials in the field of rare neurometabolic disoders would benefit from evaluation against clinical outcome variables instead of biochemical surrogate parameters and must be carefully matched against variables that have a known impact on the clinical outcome.

    References

    1. Posset R, Gropman AL, Nagamani SCS, et al; Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. Impact of diagnosis and therapy on cognitive function in urea cycle disorders. Ann Neurol 2019;86(1):116–128; [Epub ahead of print] 10.1002/ana.25492

    2. Posset R, Garbade SF, Boy N, et al; Additional individual contributors of the UCDC and the E-IMD consortium. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-a successful strategy for clinical research of rare diseases. J Inherit Metab Dis 2019;42(1):93–106


    #

    No conflict of interest has been declared by the author(s).